Benign prostatic hyperplasia (BPH) is a benign neoplasm found primarily in older males, see H. Lepor, Urologic Clinics of North America, 17, No. 3, 651-659 (1990). BPH clinical manifestations include bladder outlet obstruction resulting from enlargement of the prostate gland. The condition is most often treated by transurethral prostatectomy, see H. Lepor, et al. The Journal of Urology, 148, 1467-1474 (1992).
The prostate has been demonstrated to be rich in alpha 1 (.varies.-1) adrenergic receptors, see s. Raz, et al, British Journal of Urology, 45, 663-667 (1973). It has been reported that BPH can be treated with an .varies.-1 adrenergic receptor blocker, which may act by relaxing the tension of prostate smooth muscle, thus relieving the symptoms of infravesical obstruction, see H. Lepor et al, supra at 1473 and Forray et al., Molecular Pharmacology, 45, 703-708 (1994). Recently the .varies.-1 adrenergic receptor mRNA from human prostate has been analyzed and three subtypes have been identified: .varies.-1B, .varies.-1C and .varies.-1D, with .varies.-1C comprising 70% of the mRNA. In August of 1994 the nomenclature of the .varies.-1B, .varies.-1C and .varies.-1D subtypes of the alpha adrenergic receptors were renamed as .varies.-1B, .varies.-1A and .varies.-1D respectively, see J. Med. Chem., vol. 38 No. 10, 1579-1581 (1995) and Ford et al. Trends Pharmacol. Sci., 1994, 15, 167-170. In the present invention, the old nomenclature .varies.-1C is used to define that subtype adrenergic receptor that is currently referred to as .varies.-1A under the aforementioned August 1994 nomenclature.
Different adrenergic receptors may account for the cardiovascular and central nervous system side effects caused by nondiscriminator blockage of .varies.-1 adrenergic receptor subtypes, see D. T. Price, et al, The Journal of Urology, 150, 546-551 (1993) and PCT Application WO 94/10989. .varies.-1 adrenergic antagonists which bind selectively to the .varies.-1C adrenergic receptor subtype preferentially over the .varies.-1B and .varies.-1D subtypes have been claimed as useful in the treatment of BPH, see PCT Application WO 94/10989, supra. Testosterone 5.varies.-reductase inhibitors such as Proscar.TM. (Merck) have been shown to be useful in the treatment of a variety of androgen responsive diseases such as BPH and prostate cancer, see Frye, et al, U.S. Pat. No. 5,302,589, PCT Application WO 94/10989, supra. Additionally, .varies.-1 adrenergic receptor antagonists and dopamine D.sub.2 antagonists in combination have been shown to be useful as an antipsychotic treatment, see Hrib, et al, J. Med. Chem., 37, 2308-2314 (1994). .varies.-1-adrenergic antagonists have also been shown to differentially control serotonin release in the hippocampus and striatum, see Rouquier, et al, Eur. J. Pharmacol., 261(1-2), 59-64 (1994), have an effect on susceptibility to malignant arrhythmias, see Billman, J. Cardiovasc. Pharmacol., 24(3), 394-402 (1994), to possess dopamine receptor agonist activity and 5-HT receptor antagonist activity, see PCT patent application WO 9305035, to effect hyperthermia and hyperglycemia, see Nonogaki K., et al, Eur. J. Pharmacol.,262(1-2):177-180 (1994), to have a role in treatment of obstructive detrusor instability, see C. R. Chapple, et al, Brit. J. of Urology, 73, 117-123 (1994), and to have hemodynamic effects in cirrhotic patients with portal hypertension, see Albillos A, et al, Hepatology, 20(3): 611-617 (1994). .varies.-1-adrenergic agonists have been shown to precondition rabbit ischemic myocardium independent of adenosine by direct activation of protein kinase, see Tsuchida, et al, Circ. Res., 75(3): 576-585 (1994).
Compounds which modulate .varies.-1-adrenergic subtype response have additionally been implicated as useful for treatment of conditions such as hypertension, see U.S. Pat. No. 4,440,769, ischemic heart disease, and psychoses, see Japanese Patent JP 03264579,congestive heart failure, see PCT application WO 92/00741, cerebral angiopathy, see Japanese Patent JP03264579, sympathetically maintained pain in peripheral tissues, see PCT application WO 92/14453 and 91/2806; allergies, hypolipemia, peripheral vascular disorders and glaucoma, see French Patent FR 2574401, thrombosis and asthma, see European Patent 62596, dysuria and pollakiuria, see Japanese Patent 03090027, bronchial spasms, hemorrhoids and nasal congestion, see South African Patent ZA 8502785.
Furthermore, .varies.-1-adrenergic subtypes have been shown to have a role in mediating adrenergic vasoconstiction in kidney of two kidney, one-clip Goldblatt and deoxycorticosterone acetate-salt hypertensive rats, see Sattar, et al, J. Cardiovasc. Pharmacol. 24(3), 420-428 (1994), to have analgesic potency after systemic administration in amphibians, see Brenner, et al, J. Pharmacol, Exp. Ther., 270(2)., 540-545 (1994), to be involved in the effects of hippocampal vasopressinergic treatment on retrieval and relearning, see metzger, et al, Behav. Neural. Biol., 62(2), 90-99 (1994), to have a role in sleep-wakefulness and body temperature regulation Brain Res. Bull., 35(2), 171-177 (1994), to be involved with cardiac myocytes following coronary artery constriction in rats, see Cheng, et al, Cardiovasc. Res., 28(7), 1070-1082 (1994), to mediate biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy, see J. Biol. Chem., 268, 15374 (1993), to be involved with phasic and tonic vasoconstrictor responses, see Wong P. C. , et al, Eur. J. Pharmacol;.262(1-2):185-188 (1994), to have a role in human liver during intraabdominal sepsis, see Hwang T, et al, Hepatology; 20(3): 638-642 (1994), to modulate phosphatidylinositol cycle in cultured rat cardiomyocytes, see Van Heugten H, et al, J. Mol. Cell Cardiol. 26(8);1081-1093 (1994), and to be involved in glucose release and thus diabetes, see Capusso, A., et al, Gen. Comp. Endocrinol., 95 (3), 457-463 (1994).
Piperazinyl oxazole compounds are known and have been described for use as anti-inflammatory, analgesic and antihistamine agents. Publications disclosing piperazinyl oxazoles representative of the compounds known in the art include a number of Mitsubishi Chemical Industry Japanese patent applications such as JA-0955423 (1977); JA-095919 (1977); JA-020326 (1976); JA-095422 (1977); and, JA-096385 (1977). The Institute Farmacologico Serona SpA. has published work with amino oxazole compounds and references disclosing such compounds are JA-4602020-0 (1971); and FR 1,538,009 (1996).
The oxazole compounds of the present invention selectively inhibit the .varies.-1c adrenergic receptor subtype and are therefore useful in the treatment of BPH and other obstructive conditions in which urination is difficult or strained.